Review Article
Theme:Sterile Products:Advances and Challenges in Formulation,Manufacturing,Devices and Regulatory Aspects Guest Editors:Lavinia Lewis,Jim Agalloco,Bill Lambert,Rusll Madn,and Mark Staples
Injectable Lipid Emulsions —Advancements,Opportunities and Challenges
Ketan Hippalgaonkar,1Soumyajit Majumdar,1,2and Viral Kansara 3,4
Received 19May 2010;accepted 20September 2010;published online 26October 2010
Abstract.Injectable lipid emulsions,for decades,have been clinically ud as an energy source for hospitalized patients by providing esntial fatty acids and vitamins.Recent interest in utilizing lipid emulsions for delivering lipid soluble therapeutic agents,intravenously,has been continuously growing due to the biocompatible nature of the lipid-bad delivery systems.Advancements in the area of novel lipids (olive oil and fish oil)have opened a new area for future clinical application of lipid-bad injectable delivery systems that may provide a better safety pro file over traditionally ud long-and medium-chain triglycerides to critically ill patients.Formulation components and proce
ss parameters play critical role in the success of lipid injectable emulsions as drug delivery vehicles and hence need to be well integrated in the formulation development strategies.Physico-chemical properties of active therapeutic agents signi ficantly impact pharmacokinetics and tissue disposition following intravenous administration of drug-containing lipid emulsion and hence need special attention while lecting such delivery vehicles.In summary,this review provides a broad overview of recent advancements in the field of novel lipids,opportunities for intravenous drug delivery,and challenges associated with injectable lipid emulsions.KEY WORDS:biodisposition;lipid emulsions;micro fluidization;parenteral formulations;sterilization.
INTRODUCTION
Over the last decade,our understanding of dias and the molecular pathways involved has incread exponentially.A structure activity-bad rational approach has helped in designing novel potent therapeutic agents.However,many of the highly promising agents are dropped from the develop-ment pipeline becau of their low aqueous solubility.In recent years injectable lipid emulsions,a heterogeneous system in which the lipid pha is disperd as droplets in an aqueous pha and stabilized by emulsifying agents,have started evolving as a feasible vehicle for the delivery of hydrophobic compounds.This drug delivery approach finds its roots in the now well-establ
ished parenteral nutrition formulations.In this review,a brief overview of the paren-teral lipid emulsions and the various facets in the develop-ment of injectable lipid emulsions for drug delivery has been discusd.
EVOLUTION OF PARENTERAL NUTRITION EMULSIONS
ozoneEnglish naturalist William Courten,in 1678–1679,first attempted an intravenous administration of olive oil in dogs which resulted in pulmonary embolism (1,2).Later in 1873,Edward Hodder infud milk into cholera patients;two out of three patients recovered.However,later studies found that infusion of milk caud vere adver effects (1).In 1904Paul Friedrich infud total parenteral nutrition consisting of fat,peptone,gluco,and electrolytes,subcutaneously,in humans.However,pain associated with this route of admin-istration was so vere that subcutaneous total parenteral nutrition administration was not considered for further development (1,3).With time it was realized that fat could be given intravenously only in the form of emulsions.Between 1920and 1960,a large number of emulsions were prepared with varying compositions (oils and surfactants).Lipomul®(15%cotton ed oil,4%soy phospholipids,0.3%poloxamer 188(w /v ))was the first intravenous fat emulsion introduced in the USA in the early 1960s (2,4).However,it was later withdrawn from the market due to vere adver reaction (2,5,6).Intralipid®(100%soybean oil:1.2%
egg phospholipid),after around 14years of safe clinical u in European countries,was finally approved for u in the USA in the year 1975(5).Currently,two types of emulsions,one consisting of 100%soybean oil (Intralipid®and Liposyn III®)and the other a 50/50blend of soybean oil and saf flower oil (Liposyn II®),are marketed in the USA.
1
Department of Pharmaceutics,University of Mississippi,Oxford,Mississippi 38677,USA.2
Rearch Institute of Pharmaceutical Sciences,University of Mississippi,Oxford,Mississippi 38677,USA.3
RNAi Delivery and Process Development,Biologics and Vaccines,Merck Sharp &Dohme Corp,770Sumneytown Pike,West Point,Pennsylvania 19486,USA.4
To whom correspondence should be addresd.(e-mail:viral_)
AAPS PharmSciTech,Vol.11,No.4,December 2010(#2010)DOI:10.1208/s12249-010-9526-5
1530-9932/10/0400-1526/0#2010American Association of Pharmaceutical Scientists
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Long-chain triglyceride(LCT)(e.g.,soybean oil and safflower oil)bad emulsions have been widely ud in the clinical tting for over40years now.The lipids provide a rich source of non-gluco bad calories(7),esntial fatty acids such as linoleic(ω-6polyunsaturated fatty acids(ω-6PUFA)) andα-linolenic acid(ω-3PUFA),vitamins E and K(8). However,high proportions ofω-6PUFA,52–54%in soybean oil and77%in safflower oil,have raid concerns about their administration as the sole lipid source to critically ill patients and patients with compromid immune function,psis,and trauma (8).High levels ofω-6PUFA leads to incread production of arachidonic acid which in turn leads to incread synthesis of potent pro-inflammatory mediators(9),tumor necrosis factorαand interleukin-6(4).Moreover,high proportions ofω-6PUFA have been correlated with immunosuppressive actions such as impaired reticular endothelial system function and inhibition of lymphocytes,macrophages,and neutrophil functions(7), although the data are somewhat contradictory(10–12). Furthermore,the high number of double bonds inω-3PUFA andω-6PUFA,makes them prone to lipid peroxidation(6).The lipid peroxides generated can lead to cell death and cau damage to DNA,lipids,and proteins(6,7).Additionally, phytosterols,an isomer of cholesterol and another component of soybean oil,has been associated with adver effects on liver function(4,13).
An emulsion containing a1:1physical mixture of medium-chain triglyceride(MCTs;from coconut oil)and soybean oil wasfirst developed to address the problems associated with the LCTs.This emulsion(Lipofundin®) contains50%lessω-6PUFA(8).Other advantages of MCTs include greater solubilization effect,lower accumulation in adipo tissues and liver,faster clearance,and resistance to peroxidation(10,14,15).Moreover,MCTs do not promote the synthesis of pro-inflammatory mediators(14,16)and,unlike LCTs,have been suggested to improve immune function (10,17,18).Oxidation of MCTs is more rapid and complete than LCTs and is therefore a quick source of energy (14).Incidentally,rapid breakdown of MCTs may lead to ketosis,thereby limiting their u in patients with diabetes mellitus or where clinical condition may be aggravated by acidosis or ketosis(7,19).MCTs are,however,almost always ud in combination with LCTs becau MCTs are not a source of esntial fatty acids(20).Moreover,oxidation of MCTs leads to incread body temperature;incread energy expenditure, and induces toxicity in the central nervous system(21).
To avoid high blood levels of medium-chain fatty acids (MCFA)and yet provide esntial fatty acids,structured triglyceride(STs)-bad emulsions were , Structolipid®).STs consist of MCFA and long-chain fatty acids(LCFA)bound to the same glycerol backbone and are produced by chemical or enzymatic inter-esterification of MCFA and LCFA.For example,LMM-ST consists of L
man hubCFA at sn1-position and MCFA in sn2-and sn3-positions of the glycerol backbone(21).In patients with psis or multiple injuries,when compared with LCTs,STs demonstrated improved nitrogen balance and were well tolerated.No significant differences in the respiratory quotient,energy expenditure,or gluco or triglyceride levels were obrved between the LCT-and STs-treated groups(22).In a recent study,STs were obrved to generate lower plasma levels of leukocyte integrin expression,indicating lower inflammatory effect(23).Furthermore,STs have no effect on mononuclear phagocytic system function,does not stimulate pro-inflamma-tory mediator production,and alters liver function to a lesr extent than LCT-and MCT-bad emulsions(21,24).
Olive oil has also been evaluated for replacing soybean oil in order to reduceω-6PUFA(24).Literature suggests that ClinOleic®(80%olive oil and20%soybean oil)has neutral immunological effect and is well suited for patients who are at risk of immune suppression or are immune compromid(25) and demonstrates better liver tolerance compared with tho receiving MCT/LCT emulsions(26).However,large and well-designed clinical trials in target populations are required to demonstrate its advantage over LCT-and MCT-bad emulsions and to get worldwide approval(10).
Fish oil containing emulsions reprent the most recent development.Fish oil is currently found in three parenteral nutrition emulsions,Omegaven®(purefish oil emulsion); Lipoplus®(50MCT:40soya b
ean oil:10fish oil); SMOFlipid®(30MCT:30soybean oil:25olive oil:15fish oil).Fish oil is rich inω-3PUFA,particularly EPA (eicosapentaenoic acid)and DHA(docosahexaenoic acid). Theω-3PUFA’s posss significantly less inflammatory and vasomotor potential and may exert antagonistic functions (9,27).Additionally,ω-3PUFA inhibits the production of the pro-inflammatory cytokines(TNF-α,IL-6,and IL-1β)and modulates the production of the anti-inflammatory cytokine (IL-10)(9,27).Moreover,ω-3PUFA has the potential to prevent cardiac arrhythmias.The properties makefish oil an ideal component of lipid emulsions intended for critically ill patients with a variety of dias(7).
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Although adver effects have been associated with the administration of large volumes of lipids in parenteral nutrition,their potential negative effects,however,may not be as vere when ud for drug delivery considering the small amounts involved.For example,for an adult weighing 70kg the daily dosage of Intralipid®20%has been recommended as not to exceed175g of fat.In the ca of Diprivan®,an injectable anesthetic,(10mg/ml containing 10%w/v fat)for an adult in an ICU tting on a24h infusion (at a rate of6mg−1kg−1h−1),considering worst-ca scenario, the daily fat administration will not exceed100g(28). Therefore when compared with Intralipid®,1.8-fold less fat is administered.In the ca of emulsions formulated as small volume injections,the potential the side effects associated with the lipids is not an issue altogether.
APPLICATIONS OF EMULSION IN PARENTERAL DRUG DELIVERY
Following successful commercialization of parenteral nutrition emulsions,there has been a strong and continuous interest in developing emulsions as carriers for delivering oil-soluble drugs intravenously.A number of drug-containing emulsions have been introduced in the market(Table I)and veral others such as aclacinomycin A,amphotericin B, paclitaxel,docetaxel,and cyclosporine A are under develop-ment and in preclinical trials(29).
Advantages.Injectable emulsions prent a number of potential advantages as drug delivery vehicle.
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Injectable Lipid Emulsions
1.Reduction in pain,irritation,and thrombophlebitis:
The marketed formulation of diazepam(Valium®/ Assival®;Vehicle,propylene glycol/ethanol/benzyl alcohol)is frequently associated with pain,tissue irritation and venous quelae(30,31).Administration of Diazemuls®(diazepam emulsion)to2,435patients resulted in only0.4%of patient experiencing pain, with no reddening of skin or tenderness along the vein,related to the injection,in any patient(32).In ra
bbits,an emulsion formulation of diazepam caud significant reduction in local tissue reaction when compared to Assival®(31).Similarly,administration of clarithromycin in an emulsion formulation was associated with2–3-fold less pain compared to that of clarithromycin lactobionate solution formulation(33).
In a randomized study with16volunteers,Suttmann et al.obrved that in contrast to emulsion formulations,a commercial etomidate formulation(Hypnomidate®) caud four subjects to develop phlebitis or thrombo-phlebitis,within7days after injection(34).Similarly,a glycoferol–water solution of diazepam(Apozepam)has been reported to cau thrombophlebitis more fre-quently than Diazemuls®(35).
2.Reduced Toxicity:Paclitaxel(Taxol®)and Cyclospor-
ine(Sandimmune®Injection)are currently formu-lated in a mixture of Cremophor®EL and ethanol for intravenous injection.Cremophor®EL is associated with bronchospasms,hypotension,nephrotoxicity,and can cau anaphylactic reaction(36,37).Additionally, cyclosporine by itlf exhibits do-dependent neph-rotoxicity.Formulation of cyclosporine in an emulsion formulation(1.2%egg phospholipid/10%soybean oil) did not significantly affect glomerularfilt
ration rate (GFR),while Sandimmune and Cremophor®EL-reduced GFR to approximately70%and75%, respectively,of the baline level.The results indicate that a change in the vehicle may reduce the acute nephrotoxic side effects associated with cyclo-sporine in the Cremophor®EL formulation(38).In mice,paclitaxel when formulated in the form of an emulsion was demonstrated to be well tolerated and the maximum tolerated do for the emulsion formula-tion was approximately 3.5-fold higher(70mg/kg) compared to Taxol®(20mg/kg)(37).Similarly,Ampho-
tericin B in emulsion formulations has been reported to
reduce erythrocyte lysis and to prerve the monolayer
lkdintegrity of kidney cells compared with the commercial
drug formulation(Fungizone®)(39,40).
3.Improved Stability and Solubility:A number of drugs
such as clarithromycin,all-trans-retinoic acid,sodium
phenobarbital,physostigmine perilla ketone,and
oxathiin carboxanilide demonstrated improved stabil-
ity in emulsion formulation,probably due to
decread susceptibility to oxidation or hydrolysis
(41).Additionally,emulsion formulations have been
investigated for the solubilization of water-insoluble
drugs(42).
4.Targeted Drug delivery:This approach has been
recently extended to injectable lipid emulsions.The
feasibility of this approach was demonstrated by Ren
et al.in male Wistar rats wherein emulsion pre-loaded
with rec-apoE was taken up to a greater extent(70%of
the injected do)by the liver compared with the control
formulation without apoE(30%of the injected do)
打电话英文(43).Studies targeting the asialoglycoprotein receptors
localized on liver parenchymal cells and manno and
fructo receptors on non-parenchymal liver cells haveisolated system
also been reported(44,45).
Disadvantages.Although injectable emulsions prent a number of potential advantages the number of approved products is relatively low(Table I).Some of the major issues preventing a broader application of emulsions in drug delivery are:
1.LCT and MCT approved by the regulatory agencies
are not necessarily good solvents of lipophilic drugs.
2.Even if the drug shows reasonable solubility in the oil
pha,the oil pha in the emulsion system generally
does not exceed30%causing drug-loading challenges
for drugs with high do requirements.Development
of novel oils with improved drug solubility would
require extensive toxicity studies.
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3.Incorporated drugs may render the emulsion physi-
counscally unstable during storage making formulation关于祖国在我心中的演讲稿
efforts challenging.There are strict regulatory
requirements with respect to the control of droplet
size of injectable emulsions.
Table I.Reprentative list of currently marketed drug containing injectable emulsions
Product Active Ingredient Market Composition Ref Cleviprex Clevidipine Butyrate USA SO:EP:G(147,148) Diazemuls®Diazepam Europe,Canada and Australia SO:AcM:EP:G:NaOH(149,150) Diazepam-Lipuro®Diazepam Europe,Canada and Australia SO:MCT:EL:G:sodium oleate(151) Diprivan®Propofol Worldwide SO:EL:G:disodium edetate:NaOH(28,29) Etomidat-Lipuro®Etomidate Germany SO:MCT:EL:G:sodium oleate(151)
Fluosol-DA®Perfluorodecalin,
Perflurotripropylamine Worldwide EP:pluronic F68:potassium
oleate:G
(150)
Liple®Alprostadil(PEG1)Japan SO:EP:OA:G(150) Limethason®Dexamethasone Palmitate Japan,Germany SO:EL:G(29,150) Lipo-NSAID®Flurbiprofen axetil Japan SO:EL:G(29,150) Stesolid Diazepam Europe SO:AcM:EP:G(42,151) Vitalipid®Vitamins A,D2,E,K1Europe SO:EL:G(29,150) SO Soy Oil,AcM Acetylated monoglycerides,G Glycerol,MCT Medium-chain Triglycerides,EP egg phospholipid,EL egg lecithin,OA Oleic acid 1528Hippalgaonkar,Majumdar and Kansara
4.Limited number of approved safe emulsifiers to stabilize
the emulsion system,limiting the pharmaceutical scien-
tist to circumvent formulation challenges,and develop
emulsion system with desired target product profile.
INJECTABLE EMULSION COMPONENTS
Lipids
Lipids(LCTs and MCTs)approved by the regulatory agencies,alone or in combination,are generallyfirst-choice for developing drug emulsions.LCTs such as triolein,soybean oil, safflower oil,same oil,and castor oil are approved for clinical u.Approved MCTs include fractionated coconut oil, Miglyol®810,812,Neobee®M5,Captex®300(42).Solubility and stability of the active pharmaceutical ingredient,however, govern the lection of the lipid pha.MCTs have been reported to be a better solubilizer and exhibit greater oxidative stability compared to LCTs(10,14,15,46).Triglycerides with short-chain fatty acids,such as tributyrin(C4),tricaproin(C6), and tricaprylin(C8),have been reported to be better solubilizers of paclitaxel than LCTs(29,47).Vitamin E,
another lipid approved for parenteral u,has been demonstrated to solubilize a number of lipophilic drugs(48)and has been recently ud to develop an emulsion formulation of paclitaxel (29,37).The oil pha must be of high purity and free of undesirable components such as peroxides,pigments,decom-position products,and unsaponifiable matters such as sterols and polymers.Lipid peroxides,already prent or formed during storage,can rve as initiators of oxidation and destabilize compounds susceptible to oxidation.Stickley et al. demonstrated that NSC629243,an anti-HIV drug,was oxida-tively degraded in various oil phas due to prence of peroxides in the oil.The shelf-life of the drug in various oils varied from<1to>100days,depending on the type of oil and its supplier.Oxidation was inhibited by the incorporation of an oil-soluble thioglycolic acid into the oil.Therefore,oxidation of oil and drug during preparation and storage must be minimized by the addition of antioxidants such asα-tocopherol,thioglycolic acid,or by manufacturing under a nitrogen atmosphere(46,49). Emulsifiers
Emulsions are thermodynamically unstable systems and will eventually undergo physical ,aggregation, creaming,and droplet growth)over time.Emulsifiers stabilize emulsions by reducing the interfacial tension of the system and by providing enough surface charge for droplet–droplet repul-sion.The choice of emulsifier is driven by its toxicity profile, intended site of delivery,and
stabilizing potential.Natural lecithin,obtained from egg yolk,has been ud extensively to stabilize injectable emulsions(29).The emulsifiers are bio-compatible,nontoxic,and are metabolized like natural fat(30). However,hydrolysis of natural lecithin during emulsification, sterilization and storage leads to the formation of lysophospho-lipids,with detergent like properties,and caus hemolysis. Although,such effects have been rarely reported in clinics lysophospholipid levels must be controlled(50).Combination of synthetic surfactants with lecithin,u of purified lecithin,and addition of free fatty acids has been suggested to reduce the formation of lysophospholipids(46,50).Polyethylene glycol (PEG)lipids such as polyethylene glycol-modified phosphati-dylethanolamine(PEG-PE)have been ud as emulsifiers/co-emulsifiers to sterically stabilize emulsion formulations through the prence of PEG head groups at the emulsion surface (51–53).Additionally,the steric stabilization and/or incread hydrophilicity imparted by the emulsifiers have been demon-strated to reduce the affinity of the emulsion droplet for the mononuclear phagocyte systems(53).Non-ionic surfactants, especially Pluronic®F68,also hold great potential.Injectable emulsions stabilized with Pluronic®F68,either alone or in combination with phospholipids,have been shown to improve the stability of emulsions.However,long-term administration of emulsions containing Pluronic®F68has been associated with so-called“overloading”syndrome characterized by hyperlipidemia, fever,anorexia,and pain in the upper s
tomach,hemolysis,and anemia(46,54–57).Systemic toxicity,mainly hemolysis,and problems during autoclaving have limited the u of a number of,otherwi excellent,emulsifying agents(58).
Aqueous Pha
Additives such as tonicity modifiers,antioxidants and prervatives are usually added to the aqueous pha(water for injection).Tonicity adjustment can be achieved with glycerin,sorbitol,or Xylitol(46,58).Dextro is generally not ud for tonicity adjustment becau it interacts with lecithin and leads to discoloration of the emulsion(58).Buffering agents are generally not added to the emulsion becau there is the potential for buffer catalysis of the hydrolysis of lipids(46). Additionally,buffering agents consist of weak or strong electro-lytes which can affect the stability of the phospholipid stabilized emulsions.A number of electrolytes have been demonstrated to interact with charged colloids,through nonspecific and specific adsorption,causing physical alterations such as a change in the surface potential which can ultimately lead to emulsion destabilization(59).Small amount of sodium hydroxide is ud to adjust the pH of the system to around8.0before sterilization.
A slightly alkaline pH is preferred becau the pH decreas during sterilization,and on storage,due to the production of free fatty acids(FFAs)(46,58).Antioxidants such asα-tocopherol,ascorbic acid,an
d deferoxamine mesylate are generally added to prevent oxidation of the oil and drug substance(46,60).Additionally,antimicrobial agents such as EDTA,and sodium benzoate and benzyl alcohol,found in Diprivan®(AstraZeneca)and propofol injectable emulsion (Hospira,Inc.),are sometimes added to the aqueous pha to prevent microbial growth(46,61–63).
MANUFACTURING
Formulation Process
Figure1depicts the key process involved in the production of injectable lipid emulsions.Water soluble and oil-soluble ingredients are generally dissolved in the aqueous pha and oil pha,respectively.Emulsifiers,such as phosphatides,can be disperd in either oil or aqueous pha. Both phas are adequately heated and stirred to disper or
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Injectable Lipid Emulsions
dissolve the ingredients.The lipid pha is then generally added to the aqueous pha under controlled temperature and agitation (using high-shear mixers)to form a homoge-nously disperd c
oar emulsion (46,58).Coar emulsions with a droplet size smaller than 20μm generally produces unimodal and physically stable fine emulsions (64).The coar emulsion is then homogenized (using a micro fluidizer or a high-pressure homogenizer)at optimized pressure,temperature,and number of cycles to further reduce the droplet size and form fine emulsion (65,66).Factors such as type and concentration of oil pha and surfactants,operating temperature,pressure,number of cycles,etc .can in fluence the mean droplet size during high-pressure homogenization and micro fluidization.The USP <729>speci fies that through-out the shelf-life mean droplet size and PFAT 5(volume-weighted percentage of fat globules ≥5μm)of an injectable fine emulsion should be ≤500nm and ≤0.05%,respectively (67,68).For example,the mean droplet size of Intralipid 10%and 20%has been reported to be 276and 324nm,respectively (65).The pH of the resulting fine emulsion is then adjusted to the desired value and the emulsion is filtered through 1–5μm filters (64).The fine emulsions are usually packed in USP type I glass containers.Siliconized containers are sometimes ud to prevent droplet size growth (58).Plastic containers are permeable to oxygen and contain oil-soluble plasticizers and are thus usually avoided (46,58).Additionally,te flon-coated vial plugs/stoppers are usually ud to prevent oxygen permeation and softening on contact with the oil pha (46,58).The entire process (filtration/coar and fine emulsion preparation)should be carried out under nitrogen atmosphere whenever possible and especially in cas where the excipients and drugs are nsitive to oxidation (46,58,60).
Drug Incorporation Methodsfour leaf clover
Water-insoluble drugs,with or without the aid of co-solvents,can be incorporated into the emulsions by dissolving the drug in the oil pha prior to emulsi fication (de novo method)or added to pre-prepared emulsions (extempora-neous addition).For drugs that are highly oil soluble,the de novo method,which involves dissolving the therapeutic agent into the oil pha prior to emulsi fication,is usually adopted (42,69).In some cas,elevation of temperature and u of fatty acids as lipophilic counter-ions can help in the solubili-zation process (33,70).Alternately,oil-soluble drugs that are liquid at room temperature,such as halothane and propofol,can be extemporaneously added to pre-formed emulsions (e.g.,Intralipid®)whereon the drug preferentially partitions into the oil pha (42).Recently,a solvent-free novel SolEmuls®Technology has been developed that localizes the drug at the interface of the emulsion.In this approach,the drug,as ultra-fine powders/nanocrystals,is added to pre-formed emulsions (e.g.,Lipofundin®and Intralipid ®)or to coar emulsions,and the mixture is then homogenized until the drug crystals are dissolved,resulting in localization of drug at the interface (69,71,72).Amphotericin B formulated using this technology has been shown to be more effective and less toxic than the commercially available formulation (73).However,it has been suggested that in order to take advantage of emulsion dosage forms it is desirable to incorporate the drug into the innermost pha of the emulsion (70).
Drugs that are slightly soluble in oil can be incorporated into the emulsions with the aid of co-solvents (42,64).The solvents are evaporated during the manufacturing process.Another approach involves dissolving drug and phospholipids in organic solvents followed by evaporation of the organic
pha
Fig.1.Key unit operations for preparing lipid emulsions
1530Hippalgaonkar,Majumdar and Kansara
under reduced pressure in round bottomflasks to form a thin film.Upon sonication with the aqueous pha,a liposome-like dispersion is formed.Addition of the oil pha to this drug-liposome dispersion followed by emulsification results in an emulsion formulation(60).However,the u of co-solvents warrants careful asssment of drug precipitation,physical and chemical stability of emulsions and drug partitioning in the formulation(42).
Figure2depicts the emulsion structure and possible drug molecule distribution within the emulsion system.Drug may possibly get incorporated within the oil pha,aqueous pha, phospholipid rich pha(PLR)or the mesopha.Centrifuging the emulsions will parate the phas.The PLR has been suggested to be compod of phospholipids that formed a layer at the interface between the oil pha and the aqueous pha as well as excess phospholipids disperd in the emulsion system. The mesopha is thought to esntially consist of liposomes, also formed from excess phospholipids(74,75).Recently, Sila-on et al.investigated the effect of drug incorporation method(de n
ovo versus extemporaneous addition)on parti-tioning behavior of four lipophilic drugs,diazepam(logP2.23), clonazepam(logP1.46),lorazepam(logP0.99),and alprazolam (logP0.54)in parental lipid emulsions(soybean oil(10%w/w) and Epikuron®200)(74).Partitioning of diazepam was unaffected by drug incorporation method;both methods yielded high drug concentrations in the inner oil pha and PLR.On the other hand,partitioning of the less lipophilic drugs clonazepam, lorazepam,and alprazolam was dependent on the method of incorporation.De novo emulsification and extemporaneous addition resulted in higher drug localization in PLR,and aqueous and mesopha,respectively(74).
Sterilization
Sterilization of the formulations can be achieved by terminal heat sterilization or by apticfiltration.Terminal sterilization generally provides greater assurance of sterility of thefinal product(76).However,if the components of the emulsions are heat labile sterilefiltration can be ud.Sterilization byfiltration requires the emulsion droplet size to be below200nm.Recently, Constantinides et al.formulated a paclitaxel emulsion using high-shear homogenization in which the mean droplet diameter was below100nm and99%cumulative droplet size was below 200nm(37).Alternatively,aptic processing may be employed. However,this process is very cumber
some,labor intensive and requires additional process validation data and justification during regulatory submissions(46,76). CHARACTERIZATION OF INJECTABLE EMULSIONS
Droplet Size.Droplet size can have a direct impact on toxicity and stability of the emulsion system.Droplets greater than5μm can be trapped in the lungs and cau pulmonary embolism.Additionally,increa in the droplet size is thefirst indication of formulation stability issues.Therefore,droplet size and distribution are amongst the most important characteristics of an injectable emulsion(30,58).The USP <729>specifies a two tier method,namely Light scattering method and Light obscuration or extinction method for determining the mean droplet diameter and amount of fat globules comprising the large-diameter tail of the distribution (>5μm),respectively.For measurement of mean droplet size u of either dynamic light scattering also known as photon correlation spectroscopy or classical light scattering bad on Mie scattering theory is recommended.On the other hand, for determination of the amount of fat globules comprising the large-diameter tail of the globule size distribution (>5μm),expresd as volume-weighted percent of fat >5μm,u of a light obscuration or light extinction method that us single-particle(globule)optical sizing technique is recommended(67,68).Other complementary techniques such as u of optical microscopy,atomic force microscopy and electron microscopy can also be ud to determine
the Fig.2.A schematic depicting drug distribution within the emulsion system
1531 Injectable Lipid Emulsions
